About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

January 8, 2008

Rainbows and Fishing Expeditions

Posted by Derek

I came across a neat article in Nature from a group working on a new technique in neuroscience imaging. They expressed an array of four differently colored fluorescent proteins in developing neurons in vivo, and placed them so that recombination events would scramble the relative expression of the multiple transgenes as the cell population expands. That leads to what they’re calling a “brainbow”: a striking array of about a hundred different shades of fluorescent neurons, tangled into what looks like a close-up of a Seurat painting.

The good part is that the entire neuron fluoresces, not just a particular structure inside it. Being able to see all those axons opens up the possibility of tracking how the cells interact in the developing brain – where synapses form and when. That should keep everyone in this research group occupied for a good long while.

What I particularly enjoyed, though, was the attitude of the lab head, Jeff Lichtman of Harvard. He states that he doesn’t really know exactly what they’re looking for, but that this technique will allow them to just sit back and see what there is to see. That’s a scientific mode with a long history, basically good old Francis-Bacon style induction, but we don’t actually get a chance to do it as much as you’d think.

That varies by the area being under investigation. In general, the more complex and poorly understood the object of study, the more appropriate it is to sit back and take notes, rather than go in trying to prove some particular hypothesis. (Neuroscience, then, is a natural!) In a chemistry setting, though, I wouldn’t recommend setting up five thousand sulfonamide formations just to see what happens, because we already have a pretty good idea of what’ll happen. But if you’re working on new metal-catalyzed reactions, a big screen of every variety of metal complex you can find might not be such a bad idea, if you’ve got the time and material. There’s a lot that we don’t know about those things, and you could come across an interesting lead.

Some people get uncomfortable with “fishing expedition” work like this, though. In the med-chem labs, I’ve seen some fishy glances directed at people who just made a bunch of compounds in a series because no one else had made them and they just wanted to see what would happen. While I agree that you don’t want to run a whole project like that, I think that the suspicion is often misplaced, considering how many projects start from high-throughput screening. We don’t, a priori, usually have any good idea of what molecules should bind to a new drug target. Going in with an advanced hypothesis-driven approach often isn’t as productive as just saying “OK, let’s run everything we’ve got past the thing, see what sticks, and take it from there”.

But the feeling seems to be that a drug project (and its team members) should somehow outgrow the random approach as more knowledge comes in. Ideally, that would be the case. I’m not convinced, though, that enough med-chem projects generate enough detailed knowledge about what will work and what won’t to be able to do that. (There’s no percentage in beating against structural trends that you have evidence for, but trying out things that no one’s tried yet is another story). It’s true that a project has to narrow down in order to deliver a lead compound to the clinic, but getting to the narrowing-down stage doesn’t have to be (and usually isn’t) a very orderly process.

the CNS projects always seemed to me like a hopeless excersize in divine inspiration - testing the compounds in vivo, to see how fast a rat falls off a rotating drum or reaches a hiden platform in a water tank - while hoping that this animal behaviouralistic model is somewhat relevant to human condition. (I was amazed when I later learned that one can actually grow neurons in Petri dish or prepare living brain slices and see what they do.)

Brain is so complex machine that a chemist on a CNS project has a high chance going in a completely wrong direction, basing his selection on a data from a misleading assay, one that also happens to be low throughput and needs lots of compound.

We don't even know how exactly the memories are stored, how consciousnes is produced and regulated, how the pattern recognition processing works. We are barely at the stage of a kid who just cracked open a gaming console and can see lots of colored wires inside.

"how consciousnes is produced and regulated, how the pattern recognition processing works. We are barely at the stage of a kid who just cracked open a gaming console and can see lots of colored wires inside."

Excellent post, Milkshake. Having been involved in discussions with Artificial Intelligence types, I know that simply arriving at a working definition of consciousness is a can of worms.

Maybe consciousness is a like the display that you see on the monitor - it has its own refresh rate, some things are changing there depending on whats happenning inside the PC - but its all a highly processed output and there is a vast see of action hidden from the view. And whe youn you take psychoactive drugs you just are screwing with the machine so all kinds of nonsence, noise and raw stuff comes out and only then you realize the amazing processing power that is underneath of all this

Sure the world of translational medicine is more complex in CNS drugs...I mean let's face it...how do we really know if a mouse is considering "just ending it all"?

However, even for validated targets with proven CNS effects in human subjects, the hurdles for medicinal chemistry start even earlier. Bioavailability, BBB penetration, Pgp and other transporters, tissue accumulation, target sub-type selectivity etc, etc. It's all much more complex if you need to get into the brain.

So while I don't think most Lead Opt programs necessarily should "somehow outgrow the random approach", I think it's important to be very careful with the knowledge of optimizations and SAR/SPR knowledge you've actually gained along the way when brain is the target tissue.

If deciding to "go nuts" at this point, it might be best to be somewhat focused since the chance of throwing a hundred coins in the air and having all of them land in a stack is more than unlikely.

If I recall correctly the Sharpless asymmetric epoxidation reaction was one of a long string of random pots of hopeful mixtures. I think he even came very close to giving up before trying "one more experiment", or likewise came close to missing the positive result. Does anyone recall the story in more detail? I think being a scientist would be a lot more fun if we did get to play around at random a little bit more often.